Insulin regulates the metabolism and growth of most cells. The action of insulin is mediated through insulin receptor, an integral membrane glycoprotein. The functional receptor is a tetramer composed of two pairs of both subunits linked via disulfide bridges. The alpha-subunit, containing the insulin binding site, is exposed on the extracellular surface. The beta-subunit contains an extracellular, a transmembrane, and an intracellular domain. Within the intracellular domain there is a tyrosine phosphorylation site which is autophosphorylated upon binding of insulin. Autophosphorylation activates the tyrosine kinase associated with the beta-subunit which triggers a signal transduction cascade involving the phosphorylation and dephosphorylation of various cellular proteins. Noninsulin-dependent diabetes mellitus (NIDDM), a heterogeneous disorder is the most common form of diabetes. Although the molecular mechanism by which NIDDM occurs is poorly understood, it is generally believed that genetic defects in insulin signal transduction pathway and environmental factors increase the risk of developing NIDDM. In a rare form of extreme insulin resistance (Leprechaun-Minn-1), the levels of insulin receptors on the cell surface have been greatly reduced due to decrease in transcription of the receptor gene. Since the insulin receptor is a key player in insulin action, it is important to understand how its expression is regulated. The human insulin receptor (hIR) gene encodes a single transcript containing both the alpha and beta-subunits. To study the regulation of this gene, we propose to define the cis-elements required for the hormone responsiveness of its synthesis and to identify the trans-acting factors binding to these elements. Subsequently, we will characterize the important trans-acting factor(s) and clone the corresponding gene(s). This study should provide important insights into how the insulin receptor gene is regulated in the cell and help understand the cause of some forms of insulin resistance.